Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. [Blood] Journal article | | Title | Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. | | Author(s) | Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned T, Lock RB, Reynolds CP | | Institution | Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles & USC, Los Angeles, CA, United States. | | Source | Blood 2007 May 29. | | Abstract | Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of anti-apoptotic Bcl-2 (Bcl-2 and Bcl-XL) family proteins has been observed in ALL. ABT-737 is a small molecule BH3-mimetic that inhibits the anti-apoptotic Bcl-2 family proteins. We evaluated the cytotoxicity of ABT-737 in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in 7 ALL cell lines. Multi-log synergistic cytotoxicity was observed in all 7 cell lines with ABT-737 plus L-ASP or vincristine, and in 5 of 7 with ABT-737 plus dexamethasone or VXL. In leukemia cells, but not in normal lymphocytes, ABT-737 plus L-ASP induced greater mitochondrial depolarization (JC-1 staining), mitochondrial cytochrome c release, activation of Bax, Bid, and caspases (immunoblotting), and eventually apoptosis (annexin V staining), than did either drug alone. In mouse xenografts derived from ALL patients at diagnosis (ALL-7) or at relapse (ALL-19), event-free survival (EFS) was significantly enhanced with ABT-737 plus VXL relative to VXL or ABT-737 alone (P </= 0.02). Thus, ABT-737 synergistically enhanced VXL cytotoxicity in ALL cell lines via a mitochondrial death pathway and enhanced EFS in VXL-treated mice bearing ALL xenografts. Combining VXL with a BH3-mimetic warrants clinical investigation in ALL at relapse and potentially in chemotherapy-resistant ALL subgroups. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17536015 |
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